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Patent 2613053 Summary

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(12) Patent: (11) CA 2613053
(54) English Title: CRYSTALLINE FORMS OF 4-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYL-1-PIPERAZINYL)PROPOXY]-3-QUINOLINECARBONITRILE AND METHODS OF PREPARING THE SAME
(54) French Title: FORMES CRISTALLINES DE 4-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYL-1-PIPERAZINYL)PROPOXY]-3-QUINOLINECARB-ONITRILE, ET LEURS PROCEDES DE PREPARATION
Status: Granted
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 215/54 (2006.01)
  • A61K 31/4709 (2006.01)
(72) Inventors :
  • TESCONI, MARC SADLER (United States of America)
  • FEIGELSON, GREGG (United States of America)
  • STRONG, HENRY (United States of America)
  • WEN, HONG (United States of America)
(73) Owners :
  • WYETH LLC (United States of America)
(71) Applicants :
  • WYETH (United States of America)
(74) Agent: TORYS LLP
(74) Associate agent:
(45) Issued: 2015-11-24
(86) PCT Filing Date: 2006-06-28
(87) Open to Public Inspection: 2007-01-11
Examination requested: 2011-03-14
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US2006/025160
(87) International Publication Number: WO2007/005462
(85) National Entry: 2007-12-20

(30) Application Priority Data:
Application No. Country/Territory Date
60/696,381 United States of America 2005-07-01

Abstracts

English Abstract




This invention is directed to a crystalline
4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-
piperazinyl)propoxy]-3- quinolinecarbonitrile monohydrate
having an x-ray diffraction pattern wherein 2.theta. angles (°) of
significant peaks are at about:
9.19, 11.48, 14.32, 19.16, 19.45, 20.46, 21.29, 22.33, 23.96, 24.95, 25.59,
25.84, 26.55,
27.61, and 29.51, and a transition temperature of about 109°C to about
115°C.


French Abstract

La présente invention se rapporte à un monohydrate de 4-[(2,4-dichloro-5- méthoxyphényl)amino]-6-méthoxy-7-[3-(4-méthyl-l-pipérazinyl)propoxy]-3- quinolinecarbonitrile cristallin, qui présente un diagramme de diffraction selon lequel les angles 2? (°) de crêtes importantes sont d'environ : 9,19, 11,48, 14,32, 19,16, 19,45, 20,46, 21,29, 22,33, 23,96, 24,95, 25,29, 25,84, 26,55, 27,61, et 29,51, et présente également une température de transition comprise environ entre 109 ºC et 115 ºC.

Claims

Note: Claims are shown in the official language in which they were submitted.




21
WHAT IS CLAIMED IS:
1. An isolated crystalline Form 1 of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-
methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile
monohydrate
having an x-ray diffraction pattern wherein the 2.theta. angles (°) of
the significant
peaks are at about: 9.19, 11.48, 14.32, 22.33 and 25.84.
2. The crystalline form of Claim 1 wherein the 2.theta. angles (°)
of the significant
peaks are at about: 9.19, 11.48, 14.32, 19.16, 19.45, 20.46, 21.29, 22.33,
23.96, 24.95,
25.29, 25.84, 26.55, 27.61, and 29.51.
3. The crystalline form of 4-[(2,4-dichloro-5-methoxypheny)amino]-6-methoxy-
743-
(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of Claim
1,
having an x-ray diffraction pattern wherein the 2.theta. angles (°) of
significant peaks are
at about: 9.19, 9.98, 11.48, 14.32, 14.85, 15.64, 19.16, 19.45, 19.71, 20.46,
21.29,
22.33, 22.58, 23.96, 24.95, 25.29, 25.84, 26.55, 27.61, 28.42, 29.51, 30.32,
31.40, and
32.39.
4. The crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-
methoxy-7-[3-
(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of Claim
3,
having the x-ray diffraction pattern substantially as shown in Fig. 1 as
Pattern A.
5. An isolated crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-
6-methoxy-
7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of
Claim 1 having a transition temperature to a liquid of from 109°C to
115°C.
6. The crystalline form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-
methoxy-7-[3-
(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate of Claim
5,
wherein the transition temperature to a liquid is about 112°C.
7. A method of preparing 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-
7-[3-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate (Form I) of
Claim 1 comprising the step of treating anhydrous 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-
quinolinecarbonitrile with heated water.



22
8. A method of preparing 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-
7-[3-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate (Form I) of
Claim 1 comprising the step of converting polymorphs of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-
quinolinecarbonitrile, which have a x-ray diffraction pattern substantially
the same as
one of Patterns B, C, D and F, as shown in Figs. 1 and 11, by treatment with
water.
9. The method of Claim 7, wherein the water is heated to at least about
90°C.
10. The method of Claim 9, wherein the water is heated to at least about
95°C.
11. The method of Claim 8, wherein the water is at a temperature where no
heat source or
cold source is applied.
12. The method of Claim 11, wherein the water is at room temperature.
13. A pharmaceutical composition comprising a therapeutically effective
amount of a
crystalline Form I of Claim 1, which has an x-ray diffraction pattern
substantially as
shown in Fig. 1, Pattern A, wherein more than 50% by weight of the crystalline
form
is present, and a pharmaceutically acceptable carrier, for the treatment of
cancer.
14. A pharmaceutical composition comprising a crystalline Form I of Claim
1, which has
an x-ray diffraction pattern substantially as shown in Fig. 1, Pattern A,
wherein
more than 50% by weight of the crystalline form is present, and a
pharmaceutically
acceptable carrier.
15. The composition of Claim 13 or Claim 14, further comprising acetic
acid.
16. The composition of Claim 13 or Claim 14, further comprising a
detergent.
17. The composition of Claim 13 or Claim 14, further comprising from 0.5%
to 5.0% by
weight of a detergent and from 0.01% to 0.1% by weight acetic acid.
18. The composition of Claim 13 or Claim 14, further comprising about 2.0%
by weight
detergent and about 0.06% by weight acetic acid.



23
19. The composition of Claim 13 or Claim 14, wherein the pharmaceutically
acceptable
carrier is a sugar, a polyol and cellulose, or a combination thereof.
20. The composition of Claim 19, wherein the pharmaceutically acceptable
carrier is a
polyol and cellulose.
21. The composition of Claim 20, wherein the polyol is mannitol, sorbitol
or xylitol.
22. The composition of Claim 21, wherein the polyol is mannitol.
23. The composition of Claim 22, wherein the crystalline Form I of claim 1,
the mannitol
and the cellulose are individually present in amounts of from 20 to 50 percent
by
weight.

Description

Note: Descriptions are shown in the official language in which they were submitted.


CA 02613053 2015-07-29
- 1 -
TITLE
CRYSTALLINE FORMS OF 4-[(2,4-DICHLOR0-5-
METHOXYPHENYL)AMIN0]-6-METHOXY-743-(4-METHYL-1-
PIPERAZINYL)PROPDXY1-3-QUINOLINECARBONITRILE
AND METHODS OF PREPARING THE SAME
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] This invention is directed to crystalline forms of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile, methods of preparing these forms and pharmaceutical
compositions containing them. These compounds have anti-tumor activity and
therefore may be useful in treating cancers, particularly pancreatic and
prostate
cancer.
Related Background Art
[0002] 3-Cyanoquinoline derivatives have been shown to have anti-tumor
activity that may make them useful as chemoagents in treating various cancers,

including pancreatic cancer, melanoma, lymphatic cancer, parotid tumors,
Barrett's esophagus, esophageal carcinomas, head and neck tumors, ovarian
cancer, breast cancer, epidermoid tumors, cancers of the major organs, such as

CA 02613053 2007-12-27
2
kidney, bladder, larynx, stomach, and lung, colonic polyps and colorectal
cancer
and prostate cancer.
100031 In the following U.S. patents, 3-cyanoquinoline derivatives are
disclosed
and shown to possess anti-tumor activity: Nos. 6,002,008; 6,432,979; and
6,617,333.
[00041 There continues to be a need for forms of 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-713-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile that are more stable, but still possess a high degree of

solubility.
BRIEF SUMMARY OF THE INVENTION
[00051 This invention is directed to isolated polymorphs of crystalline 4-
[(2,4-
dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-
piperazinyl)propoxy]-3-quinolinecarbonitrile including Form I, Form II, Form
III, Form IV, Form V and Form VI having x-ray diffraction patterns as shown in

Figure 1 and Figure 11. A particular preferred polymorph is a monohydrate
(Form I) having an x-ray diffraction pattern wherein at least one or more, and

most preferably all, of the 20 angles ( ) of significant peaks are at about:
9.19,
11.48, 14.32, 19.16, 19.45, 20.46, 21.29, 22.33, 23.96, 24.95, 25.29, 25.84,
26.55,
27.61, and 29.51.
100061 Another aspect of this invention is a crystalline 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-743-(4-methyl-1-piperazinyl)propoxy]-3-
quinolinecarbonitrile monohydrate (Form I) having a transition temperature to
a
liquid of about 109 C to about 115 C.
[0007] The invention is also directed to pharmaceutical compositions
containing
a therapeutically effective amount of crystalline 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-743-(4-methyl-l-piperazinyppropoxy]-3-
quinolinecarbonitrile, which has an x-ray diffraction pattern substantially as

shown in Figs. 1 and 11 selected from the group consisting of Patterns A, B,
C,
D, E and F, wherein more than 50% by weight of the crystalline 4-[(2,4-
dichloro-
5-methoxyphenypamino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile present is one of the selected forms.

CA 02613053 2007-12-27
r
3
100081 This invention is also directed to methods of preparing crystalline
forms
of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-l-
piperazinyl)propoxy]-3-quinolinecarbonitrile, including the monohydrate,
alcoholates, and mixtures of both. One method of preparing 4-[(2,4-dichloro-5-
methoxyphenypamino]-6-methoxy-743-(4-methyl-1-piperazinyl)propoxy]-3-
quinolinecarbonitrile monohydrate (Form I) comprises the step of treating
anhydrous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-743-(4-methyl-
l-piperazinyppropoxy]-3-quinolinecarbonitrile, known herein as Form V, with
heated water. Another method of preparing 4-[(2,4-Dichloro-5-
methoxyphenyl)amino]-6-methoxy-743-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile monohydrate (Form I) comprises the step of converting
other polymorphs of 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-
(4-methyl- 1 -piperazinyl)propoxy]-3-quinolinecarbonitrile, which have a x-ray

diffraction pattern substantially the same as one of Patterns B, C, D and F,
as
shown in Figs. 1 and 11, by treatment with water. The water can be heated or
at a
temperature where no heat source or cold source is applied, in which case the
water would be at room temperature.
A BRIEF DESCRIPTION OF THE DRAWINGS
100091 Figure 1. The XRD scans of five different polymorphs of 4-[(2,4-
dichloro-5-methoxyphenyl)amino]-6-methoxy-743-(4-methyl-l-
piperazinyppropoxy]-3-quinolinecarbonitrile.
[00101 Figure 2. A dynamic vapor sorption isotherm plot of Form I.
[00111 Figure 3. A differential scanning calorimeter plot and a
theromogravimetric analysis plot of Form V after suspension in water for two
months and ten days at room temperature.
[0012] Figure 4. The XRD scans of Form I, Form V and the metastable hydrate
created after Form V is left suspended in water for two months and ten days at

room temperature.
[0013] Figure 5. The XRD scan of two batches of Form II.
[0014] Figure 6. The XRD scan of Form III.
[0015] Figure 7. The XRD scan of Form IV.

CA 02613053 2007-12-27
4
[0016] Figure 8. The XRD scan of Form V.
[0017] Figure 9. A differential scanning calorimeter plot and a
theromogravimetric analysis plot of Form I.
[0018] Figure 10. The XRD scan of five batches of Form I.
[0019] Figure 11. The XRD scans of Form VI (bottom), Form I (top), as a
standard, and the form resulting from exposing Form VI to hot water.
DETAILED DESCRIPTION
[0020] The present invention is directed to isolated crystalline 4-[(2,4-
dichloro-
5-methoxyphenypamino]-6-methoxy-7-13-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile, which can exist in six different forms, an anhydrous
form
and four different hydrated or alcoholated forms. As used herein the term
"isolated" means that more than 50% of the crystalline 4-[(2,4-dichloro-5-
methoxyphenypamino]-6-methoxy-743-(4-methyl-1-piperazinyppropoxy]-3-
quinolinecarbonitrile present is one of Forms I, II, III, IV, V and VI and
more
preferably at least 70% to 90% of the crystalline 4-[(2,4-dichloro-5-
methoxyphenyparnino]-6-methoxy-713-(4-methyl-l-piperazinyppropoxy]-3-
quinolinecarbonitrile present is in one of Forms I, II, III, IV, V and VI.
[0021] Form I is a monohydrate and is more stable than the other polymorph
forms. It gives substantially Pattern A when scanned by XRD as shown in Figs.
1 and 10. Form I generally does not lose water when exposed to 0% relative
humidity for 10 days, or when heated to 90 C for over 100 hours. Form I is not

hygroscopic, as it generally only gains about 0.52% weight when subjected to
about 90% relative humidity, as shown by the dynamic vapor sorption plot in
Fig.
2. Form I also possesses the highest transition temperature of all the
hydrated
forms.
[0022] Form II is also a monohydrated form as determined by Karl Fisher
analysis and when scanned by XRD gives substantially Pattern B shown in Figs.
1 and 5. Form III is a monoisopropyl alcoholate as determined by GLC and
NMR. Form IV is likely a hydrated polymorph, though its structure is unclear.
When scanned by XRD, Forms 111 and IV, give substantially Patterns C and D, as

CA 02613053 2007-12-27
shown in Figs. 6 and 7, respectively. Form VI is a methanolate form and gives
substantially XRD Pattern F, as shown in Fig. 11.
[0023] Forms II, III, IV and Form VI can all be transformed into Form I by
treatment with water, e.g. by heating in water. The water may be at room
temperature. The water may be heated to at least about 90 C, and as high as at

least about 95 C.
[0024] Form V is the anhydrous form, producing substantially Pattern E in
Figs.
1 and 8 when scanned by XRD, and has the highest transition temperature of all

the polymorphic forms, i.e., about 148 C. It is also readily converted to Form
I by
treatment with heated water. The water is heated to at least about 90 C, and
more
preferably is heated to at least about 95 C. In addition, Form V can be
converted
into a hydrated Form II by treatment with water at room temperature over a
period of 2 months, as shown by differential scanning calorimetry and
thermogravimetric analysis in Fig. 3. This hydrated form is different from
either
Form I or V, as shown by the XRD scan in Fig. 4. For this reason Form I is
viewed as the more stable form, even though Form V has the higher transition
temperature.
[0025] Shown in Table 1 are 20 angles from the x-ray diffraction patterns of
Forms II, III, IV and V. It should be understood that at least one of these
peaks
must be present in a given form, and preferably at least a majority of the
listed
peaks will be present for a given form. In a most preferred embodiment all the

peaks are present for a given form, although one skilled in the art will
recognize
that whether all the peaks are observed for a given form may be highly
dependent
on the concentration level of the form.
Table 1.
XRD 20 Angles for Patterns B (Form II), C (Form III), D (Form IV) and E (Form
V).
Form II Form III Form IV Form V
20 20 20 20
7.62 6.28 8.58 6.70
9.89 8.64 9.04 10.00
10.49 11.17 11.5 14.45

CA 02613053 2007-12-27
6
14.19 11.81 12.94 15.27
15.24 12.45 13.42 17.49
16.08 14.11 14.33 19.94
16.76 15.92 14.73 20.06
18.46 16.88 16.27 21.65
21.79 18.75 17.46 24.14
23.16 19.44 17.83 25.24
24.88 20.70 18.65 26.55
26.36 21.17 19.46
27.40 22.36 20.38
28.28 24.88 20.72
28.76 25.42 22.29
26.81 23.02
24.05
26.00
[0026] Form I is also more stable, and therefore more desirable, because it
can
withstand exposure to various environments for a prolonged period of time with

out degradation. For example, Form I has remained substantially pure and
physically unchanged after being exposed to 510 foot-candles (-5490 lux) light

for two weeks, 75% humidity at 40 C for 3 months, and 90 C for 2 weeks, as
determined by XRD and HPLC.
[0027] Form I has the highest transition temperature of all the hydrated
forms.
Typically Form I upon heating dehydrates between 95 C and 100 C and then
transitions to a liquid in the range of 109 C to 115 C, but the most likely
transition temperature, when substantially pure, is 112 C. The other hydrated
forms usually transition to a liquid between 76 C to 90 C. Table 2 shows the
transition temperatures of the various forms.
Table 2. List of different batches in different crystal forms.
Pattern Crystallization Solid to Liquid Transition
(XRD) temperatures and Comments
A refluxed in 95 C water Transitions at 112 C,
monohydrate
Acetone/water (3/1) Transitions at 112 C,
monohydrate
IPA/H20 (1/1) Transitions 109-115 C,
monohydrate, low crystallinity
Acetone/water (2/1) Transitions at 112 C,
monohydrate

CA 02613053 2007-12-27
7
Pattern Crystallization Solid to Liquid Transition
(XRD) temperatures and Comments
Acetone/water Transitions at 94 C,
monohydrate
= IPA/H20 (2/1) Transitions at 90 C,)
Converts to "I" in 95 C
water
= IPA/H20 (2/1) Transitions at 82 C, 11.5%
weight loss by TGA indicates
that it is a monoisopropyl
alcoholate
Converts to "I" in 95 C
water
= Acetone/water,(7/2) Transitions at 76 C
Converts to "I" in 90 C
water
Acetone/water Transitions at 80 C
= Acetone/water Transitions at 145 C
Converts to "I" in 95 C water
= Methanol Converts to "I" in 95 C water
100281 The XRD patterns of Forms I, II, III, Iv, V or VI can be determined by
using techniques and equipment known to those skilled in the art of analytical

chemistry and X-ray crystallography. The XRD patterns shown in Figures 1, 4,
5, 6, 7, 8 and 11 were produced using X-ray powder diffraction (Scintag Inc.,
Cupertino, CA), with voltage at 45kV, current at 40.0mA, power at 1.80kW, a
scan range (20) of 3 to 40 , scan step size of 0.02 , and a total scan time
of
22'38".
[00291 The XRD patterns shown in Figures 1, 4, 5, 6, 7, 8, 10 and 11 were
produced using powder samples. The XRD pattern for each form is unique to
that form. Each pattern is comprised of a set of diffraction peaks, which can
be
expressed in 2 theta angles, d-spacing and/or relative peak intensities.
100301 The 2 theta diffraction angles and the corresponding d-spacing values
account for the positions of the peaks found in a XRD pattern. D-spacing
values
are calculated with observed 2 theta angles and copper Kal wavelength using
the
Bragg equation. Variations in these numbers can result from using different
diffractometers and also from the method of sample preparation. However, more
variation can be expected for the relative peak intensities. Therefore,

CA 02613053 2007-12-27
8
identification of the various forms should be based upon the observed 2 theta
angles and the d-spacings, and less importance should be given to the
intensities.
[0031] Form I has at least one, preferably a majority and most preferably all,
of
the following characteristic 2 theta angles ( ) peaks: 9.19, 9.98, 11.48,
14.32,
14.85, 15.64, 19.16, 19.45, 19.71, 20.46, 21.29, 22.33, 22.58, 23.96, 24.95,
25.29,
25.84, 26.55, 27.61, 28.42, 29.51, 30.32, 31.40, and 32.39.
[0032] One skilled in the art would understand that the XRI) patterns of Forms
I,
II, III, IV, V and VI obtained as described herein could contain additional
peaks.
[0033] The water content of the forms described herein was measured by the
Karl Fisher method, which is well known to those skilled in the art, using a
756
KF Brinkmann Coulometer, with HYDRANAL-WATER Standard 1.00 used as
the standard.
[0034] The water content of the hydrated forms described herein, including
Figs.
3 and 9, was measured using thermogravimetric analysis. A Perkin Elmer
thermogravimetric analyzer was used for these analyses. The conditions were a
20mL/minute nitrogen gas purge, a scan range of 25 C to 300 C, and a scan rate

of 10 C/minute.
[0035] The hydroscopicity of the anhydrous Form V and the hydrated forms was
determined using dyanamic vapor sorption, including the plot for Form I shown
in Fig. 2. This was performed under the following conditions. RH was set at
0%,
30%, 52.5%, 75% and 90%, with the sample exposed for 3 hours at each RH for
two full cycles.
[0036] Transition temperatures and heat flow for the various forms, including
the
plot shown in Figs. 3 and 9, was determined using a Perkin Elmer differential
scanning calorimeter. The conditions were a 20mL/minute nitrogen gas purge, a
scan range of 25 C to 300 C, and a scan rate of 10 C/minute.
[0037] Pure, crystalline solids have a characteristic transition temperature,
the
temperature at which point the substance changes state, in the present case
the
solid transitions to a liquid. The transition between the solid and the liquid
is so
sharp for small samples of a pure substance that transition temperatures can
be
measured to 0.1 C. Because it is difficult to heat solids to temperatures
above
their transition temperatures, and because pure solids tend to transition over
a

CA 02613053 2007-12-27
9
very small temperature range, transition temperatures are often used to help
identify compounds. Measurements of the transition temperature of a solid can
also provide information about the purity of the substance. Pure, crystalline
solids
transition over a very narrow range of temperatures, whereas mixtures
transition
over a broad temperature range. Mixtures also tend to transition at
temperatures
below the transition temperatures of the pure solids.
[0038] The crystalline compounds of the present invention may be provided
orally, by intralesional, intraperitoneal, intramuscular or intravenous
injection;
infusion; liposome-mediated delivery; topical, nasal, anal, vaginal,
sublingual,
uretheral, transdermal, intrathecal, ocular or otic delivery. In order to
obtain
consistency in providing the compound of this invention it is preferred that a

compound of the invention is in the form of a unit dose. Suitable unit dose
forms
include tablets, capsules and powders in sachets or vials. Such unit dose
forms
may contain from 0.1 to 300 mg of a compound of the invention and preferably
from 2 to 100 mg. Still further preferred unit dosage forms contain 50 to 150
mg
of a compound of the present invention. The crystalline compounds of the
present invention can be administered orally. Such compounds may be
administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The
effective amount will be known to one of skill in the art; it will also be
dependent
upon the form of the compound. One of skill in the art could routinely perform

empirical activity tests to determine the bioactivity of the compound in
bioassays
and thus determine what dosage to administer.
[00391 The crystalline compounds of the invention may be formulated with
conventional excipients, such as a filler, a disintegrating agent, a binder, a

lubricant, a flavoring agent, a color additive, or a carrier. The carrier may
be for
example a diluent, an aerosol, a topical carrier, an aqueous solution, a
nonaqueous solution or a solid carrier. The carrier may be a polymer or a
toothpaste. A carrier in this invention encompasses any of the standard
pharmaceutically accepted carriers, such as phosphate buffered saline
solution,
acetate buffered saline solution, water, emulsions such as an oil/water
emulsion
or a triglyceride emulsion, various types of wetting agents, tablets, coated
tablets
and capsules.

CA 02613053 2014-03-04
[0040] When provided orally or topically, such compounds would be provided to
a subject by delivery in different carriers. Typically, such carriers contain
excipients such as starch, milk, sugar, certain types of clay, gelatin,
stearic acid,
talc, vegetable fats or oils, gums, or glycols. The specific carrier would
need to
be selected based upon the desired method of delivery, for example, phosphate
buffered saline (PBS) could be used for intravenous or systemic delivery and
vegetable fats, creams, salves, ointments or gels may be used for topical
delivery.
100411 The crystalline compounds of the present invention may be delivered
together with suitable diluents, preservatives, solubilizers, emulsifiers,
adjuvants
and/or carriers useful in treatment or prevention of neoplasm. Such
compositions
are liquids or lyophilized or otherwise dried formulations and include
diluents of
various buffer content (for example, Tris-HC1, acetate, phosphate), pH and
ionic
strength, additives such as albumins or gelatin to prevent absorption to
surfaces,
detergents (for example, TWEENTm 20, TWEENTm 80, PLURONICTM F68, bile acid
salts), solubilizing agents (for example, glycerol, polyethylene glycerol),
anti-
oxidants (for example ascorbic acid, sodium metabisulfate), preservatives (for

example, thimerosal, benzyl alcohol, parabens), bulking substances or tonicity

modifiers (for example, lactose, mannitol), covalent attachment of polymers
such
as polyethylene glycol, complexation with metal ions, or incorporation of the
compound into or onto particulate preparations of hydrogels or liposomes,
micro-
emulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte
ghosts, or
spheroblasts. Such compositions will influence the physical state, solubility,

stability, rate of in vivo release, and rate of in vivo clearance of the
compound or
composition. The choice of compositions will depend on the physical and
chemical properties of the compound capable of treating or preventing a
neoplasm.
[0042] The crystalline compounds of the present invention may be delivered
locally via a capsule that allows a sustained release of the compound over a
period of time. Controlled or sustained release compositions include
formulation
in lipophilic depots (for example, fatty acids, waxes, oils).
[0043] One embodiment of the composition of the present invention comprises a
therapeutically effective amount of at least one of the crystalline forms of 4-
[(2,4-

CA 02613053 2007-12-27
11
dichloro-5-methoxy-743-(4-methyl-1-piperazinyppropoxy]-3-
quinolinecarbonitrile, which has an x-ray diffraction pattern substantially as

shown in Figs. 1 and 11 selected from the group consisting of Patterns A, B,
C,
D, E and F, and a pharmaceutical acceptable carrier. In a preferred embodiment

more than 50%, more preferably at least 80%, more preferably greater than 90%
by weight of the crystalline form is Form I. A more specific embodiment is
where this composition comprises either acetic acid or a detergent, or both.
More
preferably the composition will comprise acetic acid in a weight percentage
range
of about 0.01% to about 0.1% and the detergent in a weight percentage range of

about 0.5% to about 5.0%. The most preferred embodiment of this composition
is where it is comprised of about 2.0% by weight detergent and about 0.06% by
weight acetic acid.
[0044] Another preferred embodiment of the composition of the present
invention comprises a therapeutically effective amount of at least one of the
crystalline forms of 4-[(2,4-dichloro-5-methoxy-743-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile, which has an x-ray diffraction
pattern substantially as shown in Figs. 1 and 11 selected from the group
consisting of Patterns A, B, C, D, E and F, and a pharmaceutical acceptable
carrier that is selected from a sugar or polyol or cellulose. In a preferred
embodiment more than 50%, more preferably at least 80%, more preferably
greater than 90% of the crystalline form is Form I, having a x-ray diffraction

pattern substantially the same as Pattern A, as shown in Fig. 1. A more
preferred
embodiment is where the sugar or polyol could be mannitol, sorbitol, or
xylitol,
with mannitol being the most preferred. In a more specific embodiment the
composition would contain both mannitol and cellulose, and more preferably the

crystalline forms of 4-[(2,4-dichloro-5-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile, the mannitol and the cellulose
are
individually present in amounts of about 20 to about 50 percent by weight. The

most preferred embodiments of the composition of the present invention are
shown in Table 3.

CA 02613053 2007-12-27
12
Table 3.
Contents (% w/w) of Compositions
Composition No. 1 2
Ingredients
Crystalline form of 26.32 41.67
4-[(2,4-dichloro-5-methoxy-743-(4-methy1-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile
A surfactant, such as poloxamer 3.00 3.00
A disintegrant, such as crospovidone 3.00 3.00
Cellulose, micro crystalline 25.00 25.00
Mannitol 42.18 26.83
A lubricant or stabilizer, such as magnesium stearate 0.25 0.25
[00451 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile is a weak base with an intrinsic
(neutral form) solubility of approximately 0.06 tig/mL at pH 8Ø It is
partially
ionized in de-ionized water where it dissolves to 1.8 g/mL with a resulting pH
of
7.2. Solubility is enhanced about 100-fold to 0.1 to 0.4 mg/mL with the
addition
of about 2% Tween80, a detergent. Solubility is further enhanced to 3-4 mg/mL
(-1000-fold) with the addition of about 0.06% acetic acid (in-situ acetate
salt vehicle).
The acetate formulation has the advantage of eliminating variability in
solubility
due to polymorphism (see Table 4 below).
[00461 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-l-
piperazinyl)propoxy1-3-quinolinecarbonitrile has poor water solubility and
wettability. However, due to the success in solubilizing the compound in the
in-
situ acetate salt vehicle, micronization is not required for formulation.
Furthermore, with the high solubility (>200 mg/mL) and better wettability in
stomach acid, micronization is also not required for human formulation.

CA 02613053 2007-12-27
13
Table 4. Solubility Information for 44(2,4-dichloro-5-methoxyphenyl)amino1-
6-methoxy-743-(4-methyl-l-piperazinyppropoxyl-3-quinolinecarbonitrile.
Batch Size (g) 95 50 120 54 18.5 550
Use Rat/Dog MTD(1v) Rat PK(P0) Rat MTD (PO) Dog PK(P0)
Genotoxicity Dog MTD (PO)
Water content % (10) 3.68 3.27 3.24 7.06 3.76 336.
Particle Size pm (Malverr N/D 50% = 9.87 50% 10.2 50% 11.7
50% = /0.5 50% = 8.3
90% < 20.2 90% < 30.0 90% < 24.1 90% < 29.1
90% < 20.8'
Polymorphism (XRD) Pattern A Pattem A Pattern D Pattern D
N/D Pattern A
Solubility (mg/mL2
Water 0.0018 (pH 7.2) NM* N/D* N/D* N/D N/D
2%Tween 80/03%MC 0.16 (pH 8.3) 0.20 (pH 8.4) 0.07 (pH 7.7)
0.06 (pH 7.8) N/D 0.41 (pH 7.4)
2%Tween80/0.5%MC 4.0 (pH 5.4) N/D 3.5 (pH 5.0) 2.68 (pH
5.2) N/D 4.25 (pH 5.7)
0.06% acetic acid
N/D =Not Determined. *Milled batches contained' a significant amount of fines,
which could not be removed from solution by centrifugation.
Filtration led to erroneously low measurements due to the adsorption of
solubilized 44(2,4-dichloro-5-methoxyphenyparnino)-6-methoxy-743-(4-methyl-
1-piperazinyOpropoxy]-3-quinolinecarbonitrile to the filter material.
100471 The dose provided to a patient will vary depending upon what is being
administered, the purpose of the administration, the manner of administration,

and the like. A "therapeutically effective amount" is an amount sufficient to
cure
or ameliorate symptoms of the disease being treated, such as cancer.
[0048] The crystalline compounds of this invention may be delivered alone or
in
combination with other compounds.
100491 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile was prepared as described in
Scheme 1. 7-(3-chloropropoxy)-4-[(2,4-dichloro-5-methoxyphenypamino]-6-
methoxy-3-quinolinecarbonitrile, 1, was alkylated with N-methylpiperazine in
the
presence of sodium iodide either neat or in a solvent such as ethylene glycol
dimethyl ether. This preparation has been reported in the literature,
[Boschelli, D.
H., et. al., J. Med. Chem., 44, 3965 (2001)].
Scheme 1
ci ci a 40 a
HN 07 H3C-N NH
HN
io CN CN
1101
1 H3C-N")
DETAILED DESCRIPTION OF THE DRAWINGS
100501 Figure 1. The XRD scans of five different polymorphs of 44(2,4-
dichloro-5-methoxyphenyl)amino]-6-methoxy-743-(4-methy1-1-

CA 02613053 2007-12-27
14
piperazinyl)propoxy]-3-quinolinecarbonitrile. The crystalline monohydrate,
Form I, is shown as Pattern A, while the crystalline anhydrous form, Form V,
is
shown as Pattern E. Patterns B, C and D are from three other polymorphs of 4-
[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methy1-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile, or mixture of polymorphs, which
have not been fully characterized.
[0051] Figure 2. This is a dynamic vapor sorption plot which shows that 44(2,4-

dichloro-5-methoxyphenypamino]-6-methoxy-713-(4-methy1-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate, Form I, gained only
0.52% from 0%RH to 90%RH. Therefore, this form must be considered non-
hydroscopic.
[0052] Figure 3. This is a differential scanning calorimeter (DSC) plot and a
theromogravimetric analysis (TGA) plot of Form V after suspension in water for

two months and ten days at room temperature. The low transitioning temperature

shown in the DSC and the rapid dehydration shown in the TGA indicates that
after suspension in water for two months and ten days indicates that the
anhydrate
has hydrated to a metastable hydrate crystal form.
[0053] Figure 4. XRD scans of Form I, Form V and Form V after it was
suspended in water for two months and ten days at room temperature, which
shows that the metastable hydrate which results from this exposure has a
different
structure than either Form I or Form V.
[0054] Figure 5. An XRD scan of two different batches of Form II, which is a
crystalline monohydrate of 4-[(2,4-dichloro-5-methoxyphenyl) amino]-6-
methoxy-743-(4-methyl- 1 -piperazyinyl)propoxy]-3-quinoline carbonitrile.
[0055] Figure 6. An XRD scan of crystalline 4-[(2,4-dichloro-5-methoxyphenyl)
amino]-6-methoxy-743-(4-methy1-1- piperazyinyppropoxy1-3-quinoline
carbonitrile in Form III.
[0056] Figure 7. An XRD scan of crystalline 4-[(2,4-dichloro-5-methoxyphenyl)
amino}-6-methoxy-743-(4-methy1-1- piperazyinyl)propoxy]-3-quinoline
carbonitrile in Form IV.

CA 02613053 2007-12-27
[0057] Figure 8. An XRD scan of the anhydrous crystalline form of 4-[(2,4-
dichloro-5-methoxyphenyl) amino]-6-methoxy-743-(4-methyl-1-
piperazyinyppropoxy]-3-quinoline carbonitrile, Form V.
[0058] Figure 9. This is a DSC plot and a TGA plot of Form I. The DSC plot
shows that Form I has a transitioning range of about 108 C to 120 C. The TGA
plot evidences that Form I is a monohydrate since it shows that there is
approximately a 3.5% loss of weight upon heating to 150 C.
[0059] Figure 10. An XRD scan of five batches of crystalline 4-[(2,4-dichloro-
5-methoxyphenyl)amino]-6-methoxy-743-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile monohydrate in Form I.
[0060] Figure 11. XRD scans of Form VI (bottom), Form I (top), and the form
resulting from heating Form VI in water (middle). Thus, it is shown that Form
VI can be converted from into Form I by exposure to water, like Forms II, III,
IV
and V.
100611 This invention will be more fully described in conjunction with the
following specific example, which should not to be construed as limiting the
scope of this invention.
EXAMPLE 1
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate, Form I,
from Form V.
[0062] Non-crystalline 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-
[3-(4-methyl-l-piperazinyppropoxy]-3-quinolinecarbonitrile was crystallized
from a solution of 50:50 (v/v) acetone and water to give Form V. The resulting

crystalline solid was recovered by filtration, and then suspended in water
heated
to about 80 C for approximately 5 minutes. This mixture was then filtered to
yield the titled compound and having a transitioning range of 109 C to 115 C.

CA 02613053 2007-12-27
16
EXAMPLE 2
Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-743-(4-
methyl-l-piperazinyppropoxy]-3-quinolinecarbonitrile monohydrate, Form I.
100631 4-[(2,4-Dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile (1.8 kg), isopropyl alcohol (12
L),
and water (6 L) were added to a 50-L flask under nitrogen. The mixture was
heated to 75 C and filtered through a polypropylene cloth. The mixture was
cooled to room temperature - crystallization began at about 37 C. The mixture
was cooled further to 4 C and then filtered. The cake was washed with 5 L of a

50/50 mixture of isopropyl alcohol/water (v/v). The resulting wet cake and 14
L
of water were added to a 50-L flask. The mixture was heated to 95 C and held
for
hours. The hot mixture was filtered through a polypropylene cloth, filter cake

washed with 2.5 L of water, and dried in a forced air oven at 40 C to give
1.37 kg
of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile Form I by XRD scans.
EXAMPLE 3
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-713-(4-
methyl-1-piperazinyppropoxy]-3-quinolinecarbonitrile, Form II.
100641 4-[(2,4-Dichloro-5-methoxyphenyflamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile (5 g) and 50 mL of a mixture of
2/1
isopropyl alcohol/ water (v/v) were added to a 125 mL flask, and heated to
reflux.
The mixture was cooled over night to room temperature and then to 5 C. After
filtration, the cake was washed with 15 mL of a 2/1 mixture of isopropyl
alcohol/water (v/v) and vacuum dried at 45 C to give 3.92 g of 4-[(2,4-
dichloro-
5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile, Form 11 by XRD scans.

CA 02613053 2007-12-27
17
EXAMPLE 4
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monoisopropyl
alcoholate, Form III.
[0065] 4-[(2,4-Dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxyl-3-quinolinecarbonitrile (5 g) and 40 mL of a mixture of
2/1
isopropyl alcohol/ water (v/v) were added to a 125 flask, and heated to
reflux.
The mixture was cooled over night to room temperature and filtered. The cake
was washed with 15 mL of a 2/1 mixture of isopropyl alcohol/water (v/v) and
vacuum dried at 45 C to give 4.51 g of 4-[(2,4-dichloro-5-
methoxyphenypamino]-6-methoxy-743-(4-methyl-1-piperazinyppropoxy]-3-
quinolinecarbonitrile monoisopropyl alcoholate as determined by GLC and
NMR and determined to be Form III by XRD scans.
EXAMPLE 5
Preparation of 4-[(2,4-dichloro-5-methoxyphenyDamino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monoisopropyl
alcoholate, Form III.
[0066] 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile (5 g) and 40 mL of a mixture of
2/1
isopropyl alcohol/ water (v/v) were added to a 125 flask and heated to 70 C.
The
hot mixture was filtered; the filtrate was heated to 70 C to redissolve the
material.
The mixture was cooled to room temperature. Crystallization began at about
45 C. After stirring overnight, the mixture was cooled to 5 C. The cake was
washed with 15 mL of a 2/1 mixture of isopropyl alcohol/water (v/v) and then
with 20 mL of water to give 6.58g of wet 4-[(2,4-dichloro-5-
methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-
quinolinecarbonitrile. A sample of the wet product (0.30 g) was vacuum dried
at
40 C to give 0.19 g of of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-
743-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monoisopropyl

CA 02613053 2007-12-27
18
alcoholate as determined by GLC and NMR and determined to be Form III by
XRD scans.
EXAMPLE 6
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyppropoxy]-3-quinolinecarbonitrile, Form IV.
[0067] 4-[(2,4-Dichloro-5-methoxyphenyDamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile (5 g) and 30 mL of acetone were
added to a 100-mL flask and heated to reflux to give a solution. The hot
mixture
was filtered to clarify. The small amount of residue on filter paper was
washed
with 3 ml of acetone. Water (10 ml) was added to the hot filtrate. The mixture

was cooled to 0-5 C with an ice-water bath and filtered. The cake was washed
with 15 ml of a 3/1 mixture of acetone/water (v/v) water and vacuum dried at
45 C to give 3.48 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-
[344-methyl-I -piperazinyl)propoxy]-3-quinolinecarbonitrile, Form IV by XRD
scans.
EXAMPLE 7
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, Form VI.
[0068] 4-[(2,4-Dichloro-5-methoxyphenyDamino]-6-methoxy-743-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile (10 g) and 200 mL of methanol
were heated to 65 C and held with stirring for 30 minutes. The hot mixture was

cooled to room temperature and filtered. The material obtained was washed with

80 mL Me0H and dried in vacuo to give 8.31 g of 4-[(2,4-dichloro-5-
methoxyphenypamino]-6-methoxy-743-(4-methyl-1-piperazinyppropoxy]-3-
quinolinecarbonitrile methanolate Form VI by XRD scans.

CA 02613053 2007-12-27
19
EXAMPLE 8
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyppropoxy]-3-quinolinecarbonitrile monohydrate, Form I,
from Form II.
100691 4-[(2,4-Dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyl)propoxy]-3-quinolinecarbonitrile, Form II (1.0 g) was refluxed for
16
hours with 30 ml of water. The mixture was cooled to room temperature and
filtered. The cake was washed with 10 ml of water and vacuum dried at 45 C to
give 0.89g of 44(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate, Form I by
XRD scans.
EXAMPLE 9
Preparation of 44(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate, Form I,
from Form III.
100701 44(2,4-Dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methy1-1-
piperazinyppropoxy]-3-quinolinecarbonitrile, Form III (2.0 g) was stirred for
24
hours with 40 ml of water at 95 C. The mixture was cooled to room temperature
and filtered. The cake was washed with 10 ml of water and vacuum dried at 45 C

to give 1.83g of 41(2,4-dichloro-5-methoxyphenyDamino]-6-methoxy-743-(4-
methyl-1-piperazinyppropoxy]-3-quinolinecarbonitrile monohydrate, Form I by
XRD scans.
EXAMPLE 10
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate, Form I,
from Form III.
100711 The wet 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-7-[3-(4-
methyl-1-piperazinyppropoxy]-3-quinolinecarbonitrile monoisopropyl

CA 02613053 2007-12-27
alcoholate, form III (6.28g) from example 5, and 40 mL of water were added to
a
100-mL flask.
[0072] The mixture was heated to 95 C and sampled after 3, 5, and 20 hours.
All
three samples gave of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-7-
[3-(4-methyl-l-piperazinyppropoxy]-3-quinolinecarbonitrile monohydrate, Form
I by XRD scans.
EXAMPLE 11
Preparation of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-743-(4-
methyl-1 -piperazinyl)propoxy]-3-quinolinecarbonitrile monohydrate, Form I,
from form IV.
[0073] 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile, Form IV (1.0 g) was refluxed for
24 hours with 20 ml of water. The mixture was cooled to 35 C and filtered. The

cake was washed with 10 ml of water and vacuum dried at 45 C to give 0.95 g of

of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile monohydrate, Form I by XRD
scans.
EXAMPLE 12
Preparation of 4-[(2,4-dichloro-5-methoxyphenypamino]-6-methoxy-743-(4-
methyl-1-piperazinyppropoxy]-3-quinolinecarbonitrile monohydrate, Form I,
from form VI.
[0074] 4-[(2,4-dichloro-5-methoxyphenyflamino]-6-methoxy-743-(4-methyl-1-
piperazinyppropoxy]-3-quinolinecarbonitrile methanolate, Form VI (1.0 g) was
heated with stirring for 5 hours at 95 C in 12 mL of water. The mixture was
cooled to room temperature and filtered. The cake was washed with 2 mL water
and vacuum dried at 45 C to give 0.9 g of of 4-[(2,4-dichloro-5-
methoxyphenyDamino]-6-methoxy-743-(4-methy1-1-piperazinyppropoxy]-3-
quinolinecarbonitrile monohydrate, Form I by XRD scans.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
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Title Date
Forecasted Issue Date 2015-11-24
(86) PCT Filing Date 2006-06-28
(87) PCT Publication Date 2007-01-11
(85) National Entry 2007-12-20
Examination Requested 2011-03-14
(45) Issued 2015-11-24

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Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
WYETH LLC
Past Owners on Record
FEIGELSON, GREGG
STRONG, HENRY
TESCONI, MARC SADLER
WEN, HONG
WYETH
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 2007-12-20 1 83
Claims 2007-12-20 4 152
Drawings 2007-12-20 11 242
Description 2007-12-20 20 995
Representative Drawing 2007-12-20 1 32
Cover Page 2008-03-19 1 67
Drawings 2007-12-21 9 206
Description 2007-12-27 20 829
Claims 2007-12-27 4 124
Abstract 2007-12-27 1 11
Drawings 2007-12-27 11 184
Description 2015-07-29 20 831
Claims 2014-02-18 3 106
Abstract 2014-02-18 1 40
Description 2014-03-04 20 828
Claims 2014-11-12 3 105
Representative Drawing 2015-10-23 1 28
Cover Page 2015-10-23 1 61
PCT 2007-12-20 4 166
Assignment 2007-12-20 4 110
Prosecution-Amendment 2007-12-20 17 513
Assignment 2007-12-27 5 187
Prosecution-Amendment 2007-12-27 38 1,192
Assignment 2008-03-28 4 165
Fees 2008-05-13 1 40
Prosecution-Amendment 2011-03-14 1 41
Prosecution-Amendment 2015-08-11 1 27
Prosecution-Amendment 2014-03-04 3 97
Prosecution-Amendment 2013-08-20 4 201
Prosecution-Amendment 2014-02-18 25 812
Prosecution-Amendment 2014-07-30 2 47
Prosecution-Amendment 2014-11-12 5 170
Amendment after Allowance 2015-07-29 4 110
Final Fee 2015-08-21 1 39